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26gest that in selectedwomenwith early clin-ical stagedisease, this canbemanagedwithfertility-sparing hormonal therapy.The use of progestogens can induce en-

dometrial regression and prevent the pro-gression of the disease. Oral progestogensare used to treat EC and ACH, but morerecently, the levonorgestrel-releasing in-trauterine system (LNG-IUS; Mirena,Bayer, Berkshire, UK) has also been usedsuccessfully to treat ACH.3 These optionsare also popular among clinicians forwomen who decline hysterectomy.4 Yet

Identification of literatureThe population of interest in this sys-tematic review was women with earlyclinical stage (International Federationof Gynecology andObstetrics stage I) ECor ACH, the intervention was fertility-sparing therapies, and the outcome wasevidence of disease regression, relapse,and live births. The following electronicdatabases were searched: MEDLINE(1950 to September 2011), EMBASE(1980 to September 2011), CochraneCentral Register of Controlled Trials and

2; accepted Aug. 7, 2012.

s study and I.D.G. were supported throughellbeing of Women entry-level scholarshipS022).

authors report no conflict of interest.

prints: Ioannis D. Gallos, MD, Academic Unitbstetrics and Gynaecology, Birmingham

mens Hospital, Birmingham B15 2TG,ited Kingdom. [email protected].

2-9378/free012 Mosby, Inc. All rights reserved.://dx.doi.org/10.1016/j.ajog.2012.08.011

For Editors Commentary, seetrial cancer (EC) and 239 of thesemen were younger than 45 years old

(3.2%). Often these wfertility desires becaufertility is strongly adevelopment of ECanhyperplasia (ACH).2

these women are usuearly clinical stage,EC, which carries a goditionally, it is recomwomen undergo a stagterectomy.However,m

m the Academic Unit of Obstetrics andnaecology, Birmingham Womens Hospitals Gallos, Rajkhowa, Coomarasamy, andpta), and the Pan-Birminghamnaecological Cancer Centre, City Hospitals Yap and Luesley), Birmingham, England,ited Kingdom.

ceived April 20, 2012; revised May 26,there is significant uncerContents

6.e1 American Journal of Obstetrics& Gynecology OCTOBER 2012en have stronganovulatory in-ciated with thetypical complexis known thatdiagnosed withll-differentiatedprognosis. Tra-nded that theseabdominal hys-tiple studies sug-

which makes it difficult to counsel thewomen accordingly. To ascertain the effi-cacyof these therapies,weconducteda sys-tematic review of observational studiesevaluating the regression, relapse, and livebirth rates for the treatment of EC andACH, andwe performed ametaanalysis oftheir treatment effects.

MATERIALS AND METHODSn 2007, 7536 women in the United efficacy of these therapies from observa-ENERAL GYNECOLOGY

egression, relapse, aerapy for endometrndometrial hyperplaview and metaanalynnis D. Gallos, MD; Jason Yap, MBChBvid M. Luesley, MD; Arri Coomarasamy

JECTIVE: The objective of the study was to evpse, and live birth rates of early-stage endompical complex hyperplasia (ACH) with fertility-s

UDY DESIGN: This was a metaanalysis of thevational studies with a random-effects model axplore for heterogeneity.

SULTS: Thirty-four observational studies, evalpse, and live birth rates of early-stage EC (41 women) with fertility-sparing treatment. Fnt for EC achieved a pooled regression rate of

this article as: Gallos ID, Yap J, Rajkhowa M, et ad live birth rates wil cancer and atypicaa: a systematicisadhurima Rajkhowa, MD;D; Janesh K. Gupta, MD

te the regression,al cancer (EC) anding treatment.

portions from ob-ameta-regression

ng the regression,women) and ACHility-sparing treat-2%, a relapse rate

of 40.6%, and a live birtrate was 85.6%, a relapTwenty women were dmetastatic) during followstage I EC (1.9%) from w

CONCLUSION: Fertility-sselected women can sat

Key words: atypical comfertility-sparing treatmen

gression, relapse, and live birth rates with fertility-tainty about the Wfertility-sparingcomplex

te of 28%. For ACH the pooled regressionrate of 26%, and a live birth rate of 26.3%.osed with ovarian cancer (concurrent or(3.6%) and 10 progressed to higher than

h 2 women died.

ing treatment of EC and ACH is feasible andtheir reproductive wishes.

x hyperplasia, endometrial cancer,ive births, progestogens

ring therapy for endometrial cancer and atypicaleb of Science conference proceedings

(IS20

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www.AJOG.org General Gynecology ResearchI Proceedings, 1990 to September11).A combination of medical subjectadings (MeSH) and text words wered to generate 2 subsets of citations, 1luding studies of EC (endometr*cer,* malignant endometr*) or

dometrial hyperplasia (endometr* hy-rplas,* premalignant endometr,*recancer* endometr*) and the otherluding studies of fertility-sparing thera-s such as progestogens and intrauterinevices or systems (intrauterine devicesdicated, Levonorgestrel, Mirena,trauterine progest,* LNG-IU,*ogest,* gestag,* fertility-sparing ther-, conservative therapy, hormone*rapy).These subsets were combined with therd and and limited to the wordsumans and female to generate a sub-of citations. The reference lists of allown primary and review articles weremined to identify cited articles not cap-ed by electronic searches. Language orgraphical restrictions were not appliedring the search or selection.

dy selection and data extractiondies were selected if the participantsre women diagnosed histologically

FIGURE 1Study selection process

otal number of citations retrieved from electroniference lists of primary and review articles: n =mbase=5,020; manual checking of reference lis

Citations excluded after

Full manuscripts retrieved for detailed evaluatio

Primary articles fulfilling inclusion criteria for sy

Articles excluded after rCase reports or cases leLack of original data i.e.Inappropriate populationData not extractableDuplicate publicationTotal excluded

los. Fertility-sparing therapy for endometrial cancer. Am J Oth early clinical stage EC or ACH, the (I.ervention was fertility-sparing ther-y, and the outcomes were histologicalease regression, relapse, or live birthes. Case reports or series with fewern 5 cases were excluded. Studies clas-ying women with endometrial hyper-sia in other than the World Healthassification 19945 (simple, complex,d atypical) were also excluded.tudies were selected in a 2-stage pro-s. First, the titles and abstracts fromelectronic searches were scrutinized2 reviewers independently (I.D.G.

d J.Y.), and full manuscripts of all ci-ions that met the predefined selectionteria were obtained. Second, finallusion or exclusion decisions werede on the examination of the full man-ripts. In cases of duplicates, the mostent or the most complete publications used. Any disagreements about inclu-nwere resolvedbyconsensusorarbitra-n by a third reviewer (A.C.). Two re-wers (I.D.G. and J.Y.) completed theality assessment. The Methodologicaldex for Non-Randomised StudiesINORS), which assesses the quality ofincluded studies, was implemented.6

m each study, outcome data were ex-cted in 2 2 tables by the 2 reviewers

arches and from examination of 26 (Medline=4,496; 10)

eening title and/or abstracts: n =9,477

=54

matic review: n=34

w of full text with reasons.than five n=8iews/letters n=4

n=4n=2n=2n=20

Gynecol 2012.D.G. and J.Y.). TX

OCTOBER 2012 AmericanDisease regression was defined as ak of residual EC or complex hyperpla-during follow-up endometrial sam-ng. Disease relapse was defined EC ormplex hyperplasia diagnosis duringlow-up endometrial sampling follow-an endometrial sample that showedease regression. Live births was de-ed as the birth of healthy infantsring the follow-up period, and itse was calculated as the number ofmen who had a birth of healthy in-ts divided by the number of total ofmen undergoing fertility-sparingrapy. We also counted the numberwomen who were diagnosed withncurrent or metastatic ovarian can-or upgraded disease to higher thange I and deaths from this diseasering follow-up.

tistical analysisgression, relapse, and live birth ratesre extracted from each study, and wemputed the log of the ratio and itsrresponding standard error for eachdy. We performed the metaanalysisng inverse-variance weighting to cal-late the random-effects summary esti-tes.7 We obtained an estimate of thetween-study variance with a random-ects metaanalysis. The square root ofs number is the estimated SD of thederlying effects across studies.Because we had relative measures ofect, the confidence intervals were cen-ed on the natural logarithm of theoled estimate and the limits exponen-ted to obtain an interval on the ratiole.8 Forest plots were created for eachtcome, showing individual study pro-rtions with confidence intervals (CIs)d the overall DerSimmonian-Lairdoled estimate.9 Heterogeneity of theatment effects was assessed graphi-lywith forest plots and statistically an-zed using the 2 test.10 Exploration ofcauses of heterogeneity for the live

th rate was planned according to theroductive method, and it was as-sed with the aid of meta-regression.11

tistical analyseswere performedusingta 8.0 (StataCorp, College Station,ClanS

cesthebyantatcriincmauscrecwasiotioviequIn(MtheFrotra).

Journal of Obstetrics& Gynecology 266.e2

Re

266.e3Am

ericanJournalofObstetrics

&Gynecology

OCTOBER2012TABLE

Characteristics of the studies

Author, year Recruitment

Study population

Intervention or study groups Outcomes (rates)Follow-up (median,range in months)Women treated

Investigations prior to treatmentto rule out invasion

Imaging Tumor markers

Bokhman et al, 1985 (n 19)12 Prospective G1 (n 11) or G2 (n 8) EC No No Hydroxyprogesterone 500 mg/d for at least 3 mo Regression n/a............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Cade et al, 2010 (n 16)13 Retrospective G1 EC MRI No MPA only (n 4) 60-400 mg/d, MPA 200-400mg/d with LNG-IUS (n 9), or LNG-IUS (n 3)

Regression, relapse,and live birth

27, 3134

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Duska et al, 2001 (n 12)14 Retrospective G1 EC No No Progestogens at various doses Regression, relapse,and live birth

82, 6358

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Eftekhar et al, 2009 (n 21)15 Prospective G1 EC MRI, CT, and USD CA125 MA 160 mg/d Regression, relapse,and live birth

39, 5108

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Elizur et al, 2007 (n 8)16 Prospective cohort study G1 EC MRI CA125 MA 160 mg/d (n 6), MPA 200 mg/d (n 1),or 600 mg/d (n 1) for at least 3 mo


51, 3875

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Gotlieb et al, 2003 (n 13)17 Retrospective G1 (n 11) or G2-3 (n 2)EC

MRI and CT CA125 MA 160 mg/d (n 8), hydroxyprogesterone8-12 g/d (n 2), NET 5 mg/d (n 1), MPA200-600 mg/d (n 2) for at least 3 mo


35, 10146

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Hahn et al, 2009 (n 35)18 Retrospective G1 (n 31) or G1 and focalG2 (n 4) EC

MRI, CT, and USD CA125 MA 160 mg/d (n 8) or MPA 250-1500 mg/d(n 20) or in combination (n 7)


23, 272

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Han et al, 2009 (n 10)19 Retrospective G1 (n 5) or G2 (n 2), ECor ACH (n 3)

MRI and USD CA125 MA 80-160 mg/d (n 7), MPA 20-1000 mg/d(n 3) for at least 3 mo


31.5, 10133

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Imai et al, 2001 (n 14)20 Retrospective Stage I G1 (n 5) or G2 (n 1) and stage II G1 (n 7) orG2 (n 1) EC

No No MPA 400-800 mg/d Regression, relapse,and live birth

12.9, 746

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Jadoul and Donnez, 2003 (n 7)21 Retrospective G1 EC (n 5) or ACH (n 2) No No Endometrial resection followed by GnRHanalogues


40, 2640

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Kaku et al, 2001 (n 30)22 Retrospective G1 (n 10) or G2 (n 2),EC or ACH (n 18)

MRI, CT, and USD No MPA 200-800 mg/d for EC (n 12) and 100-600 mg/d for ACH (n 18) for 3-6 mo


38.7, 1784

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Kim et al, 1997 (n 7)23 Retrospective G1 EC No No MA 160 mg/d for at least 3 mo Regression, relapse,and live birth

11.7, 330

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Laurelli et al, 2011 (n 14)24 Prospective Stage IA G1 EC MRI and USD No Hysteroscopic resection of the tumor followed byMA 160 mg/d for 6 mo (n 6) or LNG-IUS (52mg/d) (n 8) for 12 mo


n/a

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Le Digabel et al, 2006 (n 13)25 Retrospective Stage IA G1-2 (n 3) orstage IB G2-3 (n 2), EC orACH (n 8)

No No Progestogens at various doses (n 6) or LHRHanalogs (n 3) or combination of the 2 (n 2)or endometrial curettage (n 2)


50.5, 3277

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Lee et al, 2010 (n 12)26 Prospective ACH (n 1), otherhyperplasia (n 11)

No No Progesterone-releasing IUD system (20 g/d) Regression andrelapse

50.5, 2182

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Li et al, 2008 (n 5)27 Prospective ACH (n 3), otherhyperplasia (n 2)

No No Letrozole 2.5 mg/d for 3 mo Regression, relapse,and live birth

40.7, 2109

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Mao et al, 2010 (n 6)28 Prospective G1 EC MRI, CT, and USD CA125 MA 160 mg/d (n 2), MPA 250-500 mg/d(n 4)


29, 4102

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Gallos. Fertility-sparing therapy for endometrial cancer. Am J Obstet Gynecol 2012. (continued )

search

GeneralGynecologywww.AJO

G.org

ww

OCTOBER2012

American

JournalofObstetrics&

Gynecology266.e4TABLE

Characteristics of the studies (continued)

Author, year Recruitment

Study population

Intervention or study groups Outcomes (rates)Follow-up (median,range in months)Women treated

Investigations prior to treatment torule out invasion

Imaging Tumor markers

Mazzon et al, 2010 (n 6)29 Prospective Stage IA G1 EC MRI CA125 Hysteroscopic resection of the tumor followed byMA 160 mg/d for 6 m


43, 375

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Minaguchi et al, 2007 (n 31)30 Prospective Stage IaG1 EC (n 19) orACH (n 12)

MRI, CT, and USD No MPA 2.5-600 mg/d, mostly 400-600 mg/d for 6mo


55.8, 24138

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Minig et al, 2011 (n 34)31 Prospective Stage IaG1 EC (n 14) orACH (n 20)

MRI and USD CA125 LNG-IUS (20 g/d) for 12 mo and GnRH analog(3.75 mg depot) for 6 mo


43.5, 13127

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Montz et al, 2002 (n 12)32 Prospective Stage IaG1 EC (n 12) MRI and USD No Progesterone-releasing IUD (65 g/d) Regression andrelapse

47.3, 18135

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Niwz et al, 2005 (n 12)33 Prospective Stage IaG1 EC MRI and USD CA125 MPA 400-600 mg/d for at least 6 mo Regression, relapse,and live birth

60.2, 8412

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Otz et al, 2005 (n 12)34 Retrospective Stage IaG1 EC MRI, CT, and USD No MPA 600 mg/d Regression, relapse,and live birth

40, 979

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Parz et al, 2012 (n 14)35 Retrospective Stage IaG1 EC MRI No MPA 250-500 mg/d (n 10) or Provera 30 mg/d (n 2) or MA 16-240 mg/d (n 2)


98, 35176

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Perri et al, 2011 (n 27)36 Retrospective Stage I EC MRI, CT, and USD CA125 MA 160-320 mg/d (n 21), NET 5 mg/d (n 1), hydroxyprogesterone 2-3 g/wk (n 2), andMPA 100-600 mg/d (n 3)


47.9, 2573

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Randall and Kurman, 1997(n 33)37

Retrospective G1 EC (n 14) or ACH(n 19)

No No MPA 10-30 mg/d or MA 40-160 mg/d (n 29),ovulation induction (n 2), Bromocriptine(n1), oral contraceptive (n 1) for 3-12 mo


69, 25113

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Signorelli et al, 2009 (n 21)38 Prospective Stage IaG1 EC (n 11) orACH (n 10)

MRI, CT, and USD CA125, CA19.9 Natural progesterone 200 mg/d, days 14-25 Regression, relapse,and live birth

11, n/a

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Ushijima et al, 2007 (n 45)39 Prospective Stage IaG1 EC (n 28) orACH (n 17)

MRI CA125 MPA 600 mg/d with low-dose (81 mg) aspirin Regression, relapse,and live birth

76.5, 21118

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Wang et al, 2002 (n 9)40 Prospective Stage IaG1 EC MRI and USD CA125 MA 160 mg/d and tamoxifen 30 mg/d for 6 mo Regression, relapse,and live birth

39, 2469

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Wheeler et al, 2007 (n 44)41 Retrospective G1 EC (n 26) or ACH(n 18)

No No Oral progestogens (n 29) or progesterone-releasing IUD (n 15)

Regression andrelapse

48.8, 14132

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Yahata et al, 2006 (n 8)42 Prospective Stage IaG1 EC MRI and USD No MPA 1800 mg/d for at least 3 mo Regression, relapse,and live birth

34.6, 7114

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Yamazawa et al, 2007 (n 9)43 Prospective Stage IaG1 EC MRI and CT CA125 MPA 400 mg/d for at least 6 mo Regression, relapse,and live birth

82, 6358

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Yang et al, 2005 (n 6)44 Prospective Stage IaG1 EC MRI, CT, and USD No MA 160 mg/d for at least 6 mo Regression, relapse,and live birth

39, 5108

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Yu et al, 2006 (n 25)45 Retrospective Stage IaG1 EC (n 8) or ACH(n 17)

MRI, CT, and USD CA125 MPA 250-500 mg/d for EC and 100-500 mg/dfor ACH (n 22) or MA or hydroxyprogesterone(n 3)


51, 3875

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

ACH, atypical complex hyperplasia; CT, computed tomography; EC, endometrial cancer; GnRH, gonadotropin-releasing hormone; IUD, intrauterine device; LHRH, luteinizing hormonereleasing hormone; LNG-IUS, levonorgestrel-releasing intrauterine system; MA,megestrol acetate; MPA, medroxyprogesterone acetate; MRI, magnetic resonance imaging; NET, norethisterone; USD, ultrasound.

Gallos. Fertility-sparing therapy for endometrial cancer. Am J Obstet Gynecol 2012.

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26SULTSlection, characteristics and qualitythe primary studiese electronic search strategy yielded16 citations, andwe retrieved a furthercitations from our manual checkingreference lists of all primary articles.these, 9477 citations were excluded

cause they did not fulfill the selectionteria. Examination of the full text ofremaining 54 manuscripts found a

al of 34 primary studies,12-45 includ-559 women, of which 408 were diag-sed with EC and 151 with ACH, forlusion in this review (Figure 1). Thein characteristics of the 34 studies andstudy methodological index are pre-ted in the Table and Figure 2.The primary studies included womenth well-differentiated EC with 386men being classified as G1 and 22men with moderate or poor differenti-on (G2orG3). In24 studies, thewomenrolled underwent diagnostic imaging toe out myometrial invasion or distantease. In11of these 24 studies, the serum-125 marker was measured to also rulet concurrent ovarianmalignancy.The quality of the studies on the MI-RS checklist is shown in Figure 2.re in detail, half of the studies werespective cohorts (17 of 34) including

nsecutive patients (31 of 34) with ad-uate definition of outcomes (30 of 34).studies had a blinded assessment ofoutcomes or performed a prospec-

e calculation of the study size. We de-ed appropriate follow-up to be at leastears, and we found that in only 6 of 34dies, follow-upwasmore than 5 years.

gression, relapse, and live birthes of fertility-sparingatment for ECtaanalysis of the 32 studies (408men) of women with EC managedth fertility-sparing treatment foundt 301 women regressed with a pooledression rate of 76.2% (95% CI, 68.3, Figure 3). TheP value for the2 testheterogeneity was .976, indicating anignificant variability in the regressiones between the studies. In 29 of thesedies (267 women), women were fol-ed up over time with the median

ging from 11 to 76.5 months, and the rat

6.e5 American Journal of Obstetrics& Gynecologyapse rates were reported. We foundt 89 women after an initial regressionthe EC relapsed during follow-up,ich amounts to a pooled relapse rate40.6% (95% CI, 33.149.8) withoutnificant variability (P .566, FigureMetaanalysis of the 26 studies report-pregnancy outcomes showed that

m 325 women undergoing fertility-ring treatment for EC, 75 womenieved at least 1 live birth, with aoled live birth rate of 28% (95% CI,.636.3) with minimal heterogeneity .197, Figure 5).

gression, relapse, and live birthes of fertility-sparingatment for ACHr ACH, metaanalysis of the 14 studies1 women) found that 127 women re-ssed with a pooled regression rate of.6%(95%CI, 72100%, Figure 6). Thealue for the2 test forheterogeneitywas, indicating no variability in regressiones between the studies. In 13 of thesedies (126 women), women were fol-ed up over timewith themedian rang-from11 to76.5months and the relapse

IGURE 2uality assessment of the studies

0%0%

1. A clearly stated aim

2. Inclusion of consecutive patients

3. Prospective collection of data

Endpoints appropriate to the aim of the study

6

5. Unbiased assessment of the study endpoint

ollow-up period appropriate to the aim of the study

7. Loss to follow up less than 5%

8. Prospective calculation of the study size

los. Fertility-sparing therapy for endometrial cancer. Am J Obes were reported. We found that 27 (P

OCTOBER 2012men after an initial regression of theH relapsed during follow-up, whichounts to a pooled relapse rate of 26%%CI, 1837.6), again without any ob-ved variability (P .923, Figure 7). ForH, themetaanalysis of the10 studies re-rting pregnancy outcomes showed thatm 126 women, 31 women achieved atst 1 live birth, with a pooled live birthe of 26.3% (95% CI, 18.537.4%) withignificant heterogeneity (P .877,ure 8).

sisted reproduction versusontaneous pregnancym the 451 women that had fertility-ring treatment for EC or ACH, 142d assisted reproduction treatment toieve pregnancy and 56 of themieved at least 1 live birth. Thisounts to a 39.4% live birth rate. Theaining 309 women are presumed to

ve tried to spontaneously conceived 46 women achieved at least 1 liveth, with a rate of 14.9%. This differ-ce between assisted reproduction andntaneous conception in achievingive birth was statistically significant

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www.AJOG.org General Gynecology Researchfety of fertility-sparing treatmentere were 20 diagnoses of ovarian ma-nancy during follow-up (20 of 559,%), and it was not always clear fromprimary studies whether they repre-ted concurrent ovarian malignanciesmetastatic ovarian involvement fromendometrial primary neoplasm. Thee of ovarian cancer and staging was

FIGURE 3Forest plot of metaanalysis of regres

tudy

okhman (1983)ade (2010)uska (2001)

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ubtotal (95% CI)est for heterogeneity: Q= 17.463 on 31 degrees

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los. Fertility-sparing therapy for endometrial cancer. Am J Oorly reported, but 10 women were di- imosed with endometrioid adenocarci-ma of the ovary (10 of 559, 1.8%).The preoperative imaging or tumorrker investigations did not appear touce this incidence because in 11 stud-that carried out these investigations,arian malignancy was diagnosed dur-follow-up in 8 women (8 of 200, 4%)

mpared with 13 studies in which only

n rates for fertility-sparing treatmen

reedom (p=0.976)

79 [48,131]63 [34,116]75 [39,144]

100 [50,200]100 [58,172]

100 [48,210]

76.2 [68, 85.3]

Regressiof s Rates [95% CI]

60 [19,186]75 [39,144]57 [21,152]

100 [59,169]60 [19,186]

100 [32,310]67 [25,178]

100 [45,223]78 [46,131]57 [29,114]

42 [17,100]

89 [60,133] 71 [38,133] 55 [25,121] 64 [38,107] 89 [44,178]

33 [16,70] 88 [42,184] 78 [37,163] 67 [25,178] 75 [34,167]

30%20%10%0%

86 [54,136]

63 [41,95]

57 [29,114]

93 [54,160]

100 [57,176]

Gynecol 2012.agingwas used, and therewere 5 ovar- de

OCTOBER 2012 Americanmalignancies diagnosed (5 of 217,%), and in 10 studies with no suchestigations, there were 7 ovarian ma-nancies diagnosed (7 of 142, 4.9%).There were also 10 women (10 of 559,%)diagnosedwith stage II ECorhigherer failing treatment. In 1 case therewas atal lymphatic metastasis involving theturator lymphatic node.22 There were 2

f endometrial cancer

100%

rates (Random), 95% CI

90%80%70%60%50%40%agnno

marediesovingco

ian2.3invlig

1.8aftdisob

of f

3

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8

5274536684

2

7412918968

5

4

4

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bstetaths from fertility-sparing treatment for


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26(2 of 559, 0.36%), 1 fromadiagnosis ofynchronous endometrial, ovarian, andritoneal malignancy39 and 1 from anarian malignancy on a patient who onurrence underwent only total hysterec-ywithout salpingo-oophorectomybe-se shedidnotwant tohavemenopausalptoms.34

MMENTis metaanalysis, which included 408

FIGURE 4Forest plot of metaanalysis of relaps

tudy


an (2009)


36

0

89

1

26

RelapsedTotpat

adoul (2003)aku (2001)im (2000)aurelli (2011)e Digabel (2006)i (2008)

022110

1

Mao (2010)Mazzon (2010)Minaguchi (2007)Minig (2010)Niwa (2005)

Perri (2011)

00528

9

1

1

2andall (1999)ignorelli (2009)shijima (2007)ang (2002)heeler (2007)

ahata (2005)

148417

1

1

amazawa (2007)ang (2005)u (2009)

221

ftekhar (2009) 13

Hahn (2009) 9 2

mai (2001) 3

Ota (2005) 2Park (2011) 13

los. Fertility-sparing therapy for endometrial cancer. Am J Omen with EC and 151 with ACH, sis

6.e7 American Journal of Obstetrics& Gynecologynd that the regression rates with fer-ty-sparing treatment are very encour-ng (76% for EC and 86% for ACH).additional encouraging proportionwomen choosing this treatment forserving their fertility managed toieve live births (28% of women withand 26% of women with ACH).

omen choosing assisted reproduc-e treatment had significantly betterults, regardless of the initial diagno-

ates for fertility-sparing treatment of

freedom (p= 0.566)

38 [12, 116]46 [21, 103]

0 [0, 114]

40.6 [33.1, 49.8]

Relapse f

ts Rates [95% CI]

0 [0, 266] 22 [6, 89]

50 [13, 200] 7 [1, 51]

33 [5, 237] 0 [0, 266] 0 [0, 200] 0 [0, 133]

36 [15, 86] 25 [6, 100]

67 [33, 133]

38 [20, 72] 10 [1, 71]

67 [25, 178] 57 [29, 114] 50 [19, 133] 14 [2, 101]

100 [48, 210] 29 [7, 114]

50 [13, 200] 17 [2, 118]

30%20%10%0%

17 [5,52]

41 [21, 79]

38 [12, 116]

40 [10,160]23 [7,72]

Gynecol 2012.. However, the relapse rates during de

OCTOBER 2012low-up are worrying (41% for ECd 26% for ACH). The incidence ofarian malignancies in 20 womenring follow-up is also worrying (3.6%),d the preoperative imaging or CA-5 testing, even though essential, didt lower this incidence. The upgradedisease in a further 10 cases alongth distant metastases in 2 of thesees also represents a considerablek of this treatment. There were 2

dometrial cancer

100%

es (Random), 95% CI

90%80%70%60%50%40%foutiliagiAnofpreachECWtivres

folanovduan12noofwicasris

of

7

39443346482

4064877746

53

bstetaths reported.

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www.AJOG.org General Gynecology ResearchOur study provides an overview of thecacy of fertility-sparing treatment forly-stage EC and ACH and summa-es the current evidence. It has majornical relevance for young women whont to preserve their fertility. We re-ced potential publication bias by ex-ding case reports and cases series ofer than 5 cases.We contacted authorsthe primary studies for clarification ofevant information. Finally, we calcu-ed the events of the disease upgradering follow-up and adverse outcomes

FIGURE 5Forest plot of metaanalysis of live bir

tudy


an (2009)


43

5

75

1

32

Live birthsTotpat

adoul (2003)aku (2001)im (2000)aurelli (2011)e Digabel (2006)

31010

1

1

Mao (2010)Mazzon (2010)Minaguchi (2007)Minig (2010)

Perri (2011)

3411

12

11

2andall (1999)

shijima (2007)ang (2002)

ahata (2005)

3

322

1

2

amazawa (2007)ang (2005)u (2009)

320

ignorelli (2008) 4 1

ftekhar (2009) 2 2

ahn(2009) 8 3

mai(2001) 2 1

ta (2005) 2 1ark (2005) 13 1

los. Fertility-sparing therapy for endometrial cancer. Am J Oth fertility-sparing therapy. deOther systematic reviews produced aan of the observed rates, which doest take into account the specific weightthe studies and their variability.44 Theof a random-effects model to com-e the data across studies helps to con-l for differences between the studies.wever, because the studies includedthis metaanalysis are all observationaldies, there is an added layer of poten-l of bias that is introduced. Hence, theength of the findings in this review in-ding 34 studies is limited by the

rates for fertility-sparing treatment

freedom (p=0.197)

50 [19, 133] 23 [7, 72]

71 [30, 172]

28 [21.6, 36.3]

Live birthf

ts Rates [95% CI]

60 [19, 186] 8 [1, 59]

0 [0, 114] 7 [1, 51]

0 [0, 160] 50 [16,155]

67 [25, 178] 6 [1, 39] 7 [1, 51]

44 [25, 78] 21 [7, 66]

14 [4, 42] 22 [6, 89]

25 [6, 100] 33 [11, 103] 33 [8, 133] 0 [0, 100]

30%20%10%0%

36 [14, 97]

10 [2, 38]

23 [11, 46]

14 [4, 57]

17 [4, 67] 29 [11, 76]

Gynecol 2012.arth of primary literature.46 tre

OCTOBER 2012 AmericanThe unstable study estimates and widenfidence intervals because of smallmbers along with the risk of bias inst of the studies because of their studysign and short-term follow-up reducestrength of our inferences. Specifi-

ly, the relapse and live birth rates mayve to be higher if women were fol-ed up for at least 5 years followingir diagnosis.47 It is reported that re-se may be more likely for obesemen,47 but the primary studies in-ded in our analysis did not report the

ndometrial cancer

100%

tes (Random), 95% CI

90%80%70%60%50%40%menoofusebintroHoinstutiastrclu

conumodethecalprolowthelapwoclu

of

5

527456684

74

298968

1

24

bstetatment effects taking into account


obtypdifrat

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26esity. It is also plausible that differentes and doses of hormones may have aferential effect on disease regressiones.We encountered a large clinical varia-n in fertility-sparing treatment regi-ns, which prevented us from makingmparisons. The variability across thedies was found to be statistically low,t this test may not be a reliable evalu-on of the clinical variation in the stud-because of small sample sizes. Ameta-alysis found that regression is higherth LNG-IUS than oral progestogensACH,3 and it is a popular choiceong clinicians in which hysterectomyot possible.4

We believe that even though the diag-sis of EC or ACH in women who wantpreserve fertility is uncommon, it isanagement dilemma for clinicians.

rtility-sparing treatment does repre-t an option for these women with en-uraging results but also importantks. Women wanting to pursue this

FIGURE 6Forest plot of metaanalysis of relapstreatment of atypical complex endom

tudy

an (2009)


15

3

127

RegressedTotpat

adoul (2003)aku (2001)

ee(2010)i (2008)

11

15

12

Minaguchi (2007)Minig (2010)Montz (2002)

121

11199

andall (1999)ignorelli (2009)shijima (2007)heeler (2007)

1111

176

165

u (2009) 117

e Digabel (2006) 5

los. Fertility-sparing therapy for endometrial cancer. Am J Oatment would need to be counseled EC

6.e9 American Journal of Obstetrics& Gynecologyroughly about the benefits and thetential risks.Pretreatment investigations shouldto rule out myometrial invasion and

ncurrent ovarian cancer, even thoughre are no reliable tests for this pur-se. These should include imaging,h as transvaginal ultrasound andmputed tomography or magnetic res-ance imaging alongwith tumor serumrkers, but the limitations of these in-tigations should be taken into ac-unt. In the primary studies, these testsnot lower the incidence of ovariancer diagnosis during follow-up, butcause this is a rare outcome,wemay bederpowered to draw conclusions andalso cannot rule out a different casex across the studies.We should also point out that there iscertainty about the treatment regimend the follow-up, which is reflected inr studies in which various therapiesre used. The studies included in thisiew suggest that when a diagnosis of

ates for fertility-sparingrial hyperplasia

reedom (p= 0.990)

100 [32, 310]

85.6 [72, 100]

Regressf

ts Rates [95% CI]

50 [7, 355]83 [50, 138]

100 [14, 710]100 [25, 400]

92 [51, 166]95 [61, 149]75 [39, 144]89 [56, 144]60 [27, 134]94 [58, 154]50 [21, 120]

100 [62, 161]

30%20%10%0%

63 [26, 150]

Gynecol 2012.or ACH has been made, this should wo

OCTOBER 2012treated for at least 3 and up to 12nths. A repeat biopsy should confirmression before women attempt to getgnant.Considering the high relapse rate ofdisease once the treatment is stoppedd the potential of disease progression,is sensible to recommend to thesemen to undergo staging hysterectomyth bilateral salpingo-oophorectomy.is should be recommended to womence their family is complete or if fertil--sparing treatment fails, either be-se of failure in regressing their diseaserelapse. If regression is achieved,would also recommend that thesemen be encouraged to undertake as-ted reproduction treatment to maxi-ze their chances of a live birth andnimize time before a hysterectomy,ich could prevent them from relapse.mediate assisted reproduction treat-nt avoids prolonged unopposed es-gen stimulation, which could cause

100%

rates (Random), 95% CI

90%80%70%60%50%40%thopo

aimcotheposuccoonmavescodidcanbeunwemi

unanouwerev

bemoregpre

theanitwowiThonitycauorwewosismimiwhImmetro

bstetmen to relapse.48

SH

STest for heterogeneity: Q=5.856 on 12 degrees of freedom (p= 0.923)

100%

K

MMMR

90%80%70%60%50%40%30%20%10%0%

L

SUW

Gal

S

H

ST

JK

RSUY

L

Gal

www.AJOG.org General Gynecology Researchlos. Fertility-sparing therapy for endometrial cancer. Am J Obstet Gynecol 2012.

FIGURE 8Forest plot of metaanalysis of live birth rates for fertility-sparingtreatment of atypical complex endometrial hyperplasia

tudy

an (2009)

ubtotal (95% CI)est for heterogeneity: Q=4.480 on 9 degrees of freedom (p=0.877)

3

126

1

31

33 [5, 237]

26.3 [18.5, 37.4]

100%

Live birth rates (Random), 95% CILive birthsTotal of patients Rates [95% CI]

adoul (2003)aku (2001)

218

14

50 [7, 355]22 [8, 59]

Minaguchi (2007)Minig (2010)

1220

26

17 [4, 67]30 [13, 67]

andall (1999)ignorelli (2009)shijima (2007)

191017

354

16 [5, 49]50 [21, 120]

24 [9, 63]u (2009) 173 18[6, 55]

90%80%70%60%50%40%30%20%10%0%

e Digabel (2006) 82 25 [6, 100]

los. Fertility-sparing therapy for endometrial cancer. Am J Obstet Gynecol 2012.FIGURE 7Forest plot of metaanalysis of regression rates for fertility-sparingtreatment of atypical complex endometrial hyperplasia

tudy

an (2009)

ubtotal (95% CI)

3

126

0

27

0 [0, 266]

26 [18, 37.6]

Relapse rates (Random), 95% CIRelapsedTotal of patients Rates [95% CI]

aku (2001) 150 0 [0, 53]

Lee (2010)Li (2008)

12

01

0 [0, 799]50 [7, 355]

inaguchi (2007)inig (2010)ontz (2002)

1119

9

441

36 [14, 97]21 [8, 56]11 [2, 79]

andall (1999) 173 18 [6, 55]

e Digabel (2006) 51 20 [3, 142]

ignorelli (2009)shijima (2007)heeler (2007)

616

5

142

17 [2, 118]25 [9, 67]

40 [10, 160]Yu (2009) 176 35 [16, 79]OCTOBER 2012 American Journal of Obstetrics& Gynecology 266.e10

lowtomanrel

tioeasbirwibyeaslowexacoqucliintshoholontre

ACWesup

REF1. OticsnosriesOffi2. EPAriskfert3. GpapOraintra sOb4. GrasendKinste5. IthohypBla5th6. SPanonand2007. Min hLon

8. DAn(chchrter200AvaAc9. Dclin10.see32211.riskSta12.Visnomdia13913.D.do14.Chwo20015.jaeacewitpercer16.BeizativeFer17.Ougescer18.sernanGy19.nantecpatatyCa20.Kuwitwisitat21721.meatytria1322.

merev20023.Niemapreand32024.GMendstu25.C,witmetiveFreFer26.tivesyspla20127.mayou10028.comwonom29.contivetriaSte30.al.siotomcomadeLet31.Bodevtrediffyou32.ruztreOb33.Tammenom34.Clincarand65735.


26Finally, clinicians should consider fol-ing up women who decline hysterec-y for at least 5 years or even longer

d not to underestimate the risk ofapse.In conclusion, this review of observa-nal studies found a high chance of dis-e regression and encouraging liveth rates of early-stage EC and ACHth fertility-sparing treatment followedassisted reproduction. The risk of dis-e relapse and upgrade during fol--up is considerable. Our systematicmination of the published literaturenfirms that there is only moderate-ality observational evidence to informnical practice, and results should beerpreted with caution. Our reviewuld aid the design of prospective, co-rt studies to assess the short- andg-term effects of the fertility-sparingatment. f

KNOWLEDGMENTthank Wilma Arnold for her administrativeport.

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www.AJOG.org General Gynecology ResearchOCTOBER 2012 American Journal of Obstetrics& Gynecology 266.e12

Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer ...Materials and MethodsIdentification of literatureStudy selection and data extractionStatistical analysis

ResultsSelection, characteristics and quality of the primary studiesRegression, relapse, and live birth rates of fertility-sparing treatment for ECRegression, relapse, and live birth rates of fertility-sparing treatment for ACHAssisted reproduction versus spontaneous pregnancySafety of fertility-sparing treatment

CommentAcknowledgmentReferences

jurnal kita

Documents

treatment of ec andach

seetrial cancer ec

birmingham b15

md jason yap

systematic review

endometrial regression

ited kingdom

fertilitysparing therapies